Acceptable Operating Range for the CPPs

I came across this white paper from the Product Quality Research Institute (PQRI) awhile back but only just revisited it to work on a resolution of how to justify whether a process parameter was critical or non-critical.  In their paper, the authors state that a "Critical Process Parameter  (CPP) is a process input that, when varied beyond a limited range, has a direct and significant influence on a Critical Quality Attribute (CQA).  Failure to stay within the defined range of the CPP leads to a high likelihood of failing to conform to a CQA."

The challenge is the interpretation of a "limited range".  Limited relative to what, infinity?  The normal operating range (NOR) "reflects the range over which a parameter can vary without impacting critical quality attributes".  From the previous discussions, we saw that the aggregate profile doesn't change significantly within the NOR that I specified in the model AND the variation within the host cell protein data was going to be difficult to identify given the precision of the assay.  Within the context of the discussion, the data are consistent with current thinking about definitions to process parameters.  However, I haven't defined what is meant with "limited range".

Taking a lead from the PQRI white paper, the goal of the development team is to define the limits of that "limited range"in relation to the NOR.  These ranges for the process parameters become the proven acceptable ranges (PAR), or acceptable operating range (AOR).  The development team has to define these AORs/PARs using laboratory-scale models that reflect the process at manufacturing scale.  In the worked example, there is limited manufacturing scale production data that may be used to link back to the laboratory-scale results.  In this paper, the author proposes using a one-sided specification limit to define the AOR.  Let's say, for the sake of argument, that the release specifications for the drug substance are as follows:
Aggregate: <0.95%
[HCP]: < 20 ppm

Within JMP, the prediction profiles can be output and used to generate an operating space.  In this case, the non-colored regions are allowed and the colored regions are the points at which the CQA(s) would be at risk.  Within the region bounded as less than 200 g/L of load and a load conductivity of 10-30 mS/cm, the process is expected to yield a product with CQAs that are within the release limits.

Relationship of Release Specifications to the Studied Ranges

The resulting limits would attempt to be filed:

Load Conductivity NOR:  19.5 - 20.5 mS/cm

Load Conductivity AOR:  10 - 30 mS/cm

Load amount NOR: 190-210 g/L

Load amount AOR: <220 g/L

Now for the pressing question: which limits do you file for your process description?  Keep in mind that the limits you file in the process description are the ones to which you, as the sponsor, are committed to sustaining during manufacturing.  The implication is that if you exceed the limits within the process description, the expectation is that the batch would be rejected.